Several lines of evidence indicate a protective effect of Mullerian inhibiting substance (MIS) for ovarian and endometrial cancers. Objectives/Hypothesis: We hypothesize that premenopuasal women's circulating MIS concentrations are inversely associated with their risk of subsequently developing epithelial ovarian and endometrial cancer. Specific Aims: 1) Prospectively determine the association of premenopausal circulating MIS levels with risk of subsequent epithelial ovarian cancer; and 2) with risk of endometrial cancer. Study Design: A prospective case-control study will be conducted nested in 9 established cohorts including the Columbia, MO Serum Bank, CLUE I and CLUE II in Washington County Maryland, New York University (NYU) Women's Health Study, Nurses' Health Study, Guernsey, UK Cohort, Northern Sweden Health and Disease Study, European Prospective Investigation into Nutrition and Cancer (EPIC), Hormones and Diet in the Etiology of Breast Cancer (ORDET), and Shanghai Women's Health Study. The 9 cohorts include women who provided a blood sample at d 45 years old while premenopausal and subsequently developed invasive ovarian cancer (n=305) or endometrial cancer (n=373). For each of these cases, two controls will be selected matched on cohort, age and date of blood collection. MIS will be measured using a commercially available and validated MIS enzyme-linked immunosorbent assay (ELISA). Analysis will be conducted using conditional logistic regression. Significance: The proposed study will prospectively evaluate the association of a novel biomarker, MIS, with risk of developing ovarian and endometrial cancers. Results of the proposed study will increase our understanding of the etiologies of these cancers. The proposed study also could potentially identify new avenues for research on ovarian and endometrial cancer risk assessment and screening. PUBLIC HEALTH RELEVANCE: Endometrial and ovarian cancers are the most common gynecological cancers in the US. The etiologies of these cancers are not well understood, but Mullerian Inhibiting Substance (MIS) is a promising biomarker of risk. Results of the proposed study will increase our understanding of the etiologies of ovarian and endometrial cancer and could potentially identify new avenues for research on approaches to risk assessment and screening.